Certain dihydropyrido(2,1-b)(1,3)benzodi-azepines and benzodiazocines

ABSTRACT

COMPOUNDS OF THE FORMULA   1,2-(-(CH2)N-(R&#39;&#39;-1,2-PHENYLENE)-N=),(R)M-1,2-DIHYDROPYRI   DINE   EXHIBIT CENTRAL NERVOUS SYSTEM STIMULATING PROPERTIES AND ACT AS MUSCLE RELAXANTS.

United States Patent O Mar. 8,1973, Ser. No. 339,258

Int. Cl. C07d 31/50 US. Cl. 260-2943 B 3 Claims ABSTRACT THE DISCLOSURE Compounds of the formula exhibit central nervous system stimulating properties and act as muscle relaxants.

This application is a continuation-in-part of Serial No. 299,986, filed Oct. 24, 1972, now abandoned.

OBJECTS OF THE INVENTION It is an object of the present invention to provide new compounds having central nervous system (CNS) stimulating activity. Another object is to provide new compounds having muscle relaxant properties. A further object is to provide intermediates for the preparation of the final compounds of the invention. Yet another object is to provide a method for the preparation of both the intermediate and ,the final compounds of the present invention. Still another object is to provide a method for the administration of the final compounds of the invention. A still further object is to provide pharamaceutical compositions containing as active ingredients the final compounds of the present invention. These and other objects of the present invention will be apparent from the following description.

SUMMARY OF THE INVENTION.

The compounds of the present invention have the following formula wherein m: may be 1 or 2;

R may be the same or different and may be hydrogen,

, halogen (F, Cl, or Br),falkyl:of from 1 to carbons,

3,825,549 Patented July 23, 1974 alkoxy of from 1 to 4 carbons, alkylthio of from 1 to 4 carbons, benzyl, phenethyl, phenyl, phenylthio, or mono-substituted phenyl wherein the substituent may be halogen (F, 'Cl, Br or 1), alkyl. of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons, or trifluoromethyl; providedthat when R is halogen, R occupies only the 3- or S-position in the original 2-aminopyridine;

R may be hydrogen, halogen F, Cl, Br or I), alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons, alkylthio of from 1 to 4 carbons, alkylsulfonyl wherein the alkyl radical has from'l to 4 carbons, phenyl, phenloxy, sulfamoyl, dialkylamidosulfonyl wherein each alkyl radical may have from 1 to 4 carbons, trifiuoromethyl, mono-substituted phenyl or mono-substituted phenyloxy wherein the substituent may be halogen (F, Cl, Br or I), alkyl of from 1 to 4 carbons, alkoxy of from 1 to 4 carbons or trifluoromethyl; and

n is 2 or 3.

The foregoing compounds possess central nervous system stimulating properties and act as muscle relaxants.

DETAILED DESCRIPTION The final compound I of the present invention may be prepared by reacting an 2-aminopyridine II with an obromophenalkylene bromide III. This reaction takes place in any solvent or solvent mixture in which the reactants can be dissolved and which has a boiling point of at least about C. Typical solvents are aromatic hydrocarbons, ethers, aliphatic alcohols or aryl-substituted aliphatic alcohols. Toluene and xylene are examples of suitable aromatic hydrocarbons. Monomethyl ether of diethylene glycol, dimethyl ether or diethylene glycol (diglyme), monomethyl ether of ethylene glycol or dimethyl ether of ethylene glycol (glyme) are examples of suitable ethers. n-Amyl alcohol is an example of a suitable aliphatic alcohol, while benzyl alcohol is an example of a suitable aryl-substituted aliphatic alcohol. Heating compounds II and III in a solvent as described above, or a mixture thereof, at temperatures from about 100 to about 140 C. for a period of several hours, typically from about 3 to about 24 hours produces a pyridinium compound IV. The latter is converted to an imino compound V by treating with a water miscible alcohol and an alkali metal alkoxidc of up to 3 carbon atoms. The reaction takes place at room temperature over a period of from about 1 to about 4 hours. Compound V may be converted to the final compound I by treating with a water miscible alcohol and an alkali metal alkoxide of up to 3 carbons in the presence of copper at a temperature of from about 60 to about for several hours, typically from about 2 to about 4 hours. Alternatively, IV may be converted directly to I by heating at a temperature of from about 60 to about 120 C. for several hours, typically from about 1 to about 4 hours in the presence of potassium carbonate and copper in a solvent such as dimethylformamide, dimethylacetamide, dichlorobenzene, trichlorobenzene, or, diethylbenzene. Preferably, however, IV may be converted directly to I by heating at a temperature of from about 60 to about 120 C. for Several hours, typically from about 1 to about 4 hours in the a 3 presence of an alkali metal bonate, tris-alkali metal phosphate, alkali metal metaborate or alkali metal tetraborate in a solvent comprising a mixture of water and a water miscible alcohol in the presence of copper. Specific examples of suitable compounds include LiOH, NaOH, KOH, RbOH, CsOH, Na2CO3, K CO Rb CO CSgCOg, Na PO K3PO4, Rb3PO4, CS3PO4, Na B2O4, NH2B407, K2B204, and K B O The ratios of water and alcohol in the mixture of water and a Water miscible alcohol are such that a homogeneous single phase system results. The foregoing reaction sequence is illustrated bythe following equations.

BHOQ,

III

The intermediates of formula III wherein n is 2 may be prepared by treating an o-brornobenzyl alcohol VI with PBr at temperatures of from about to about 100 C. for a period of from about 1 to about 6 hours. The resulting o-bromobenzyl bromide VII is then treated with sodium cyanide in the presence of water and a water miscible alcohol to yield an o-bromophenylacetonitrile VIII. Treatment of the latter with an alcohol in the presence of concentrated sulfuric acid yields the corresponding ester IX. Treatment of the latter with lithium aluminum hydride yields an o-bromophenethanol. Treatment of the latter with PBr at temperatures within the range of from about 0 to about 100 for a period of from about 1 to about 6 hours yields the corresponding o-bromophenethyl bromide XI. The foregoing reaction sequence is illustrated by the following equation -orhorr 0mm W:

PBr

lNaCN hydroxide, alkali metal car x XI The intermediates of formula III wherein n is 3 may be prepared by treating a compound. (Bf-formula XI .with sodium cyanide in the presence ofwater and a water miscible alcohol to yield an o-bromophenylpropionitrile XII. Treatment of the latter with an alcohol in the presence of concentrated sulfuric acid yields the corresponding ester XIII. Treatment of the latter with lithium aluminum hydride yields an o-bromophenpropanol. Treatment of the latter with PBr at temperatures within the range of from about 0 to about C. for a period of from about 1 to about 6 hours yields the corresponding o-bromophenpropyl bromide XV. The foregoing reaction sequence is illustrated by the following equations XIV I CHgCHzCHZ B 1' XVIII V 1) HNO2 2 AlkylSNa Treatment of the compound of formula XIX with PBr3 as shown in the sequence proceeding from X to XI, and from XI to XV yields the compound of formula XIV or XV wherein R is alkylthio.

When R is trifluorornethyl, the intermediate of formula VII may be prepared by reacting a trifluoromethylphenyl magnesium bromide XX with methyl iodide to obtain a trifluoromethyl toluene XXI. Treatment of the latter with bromine in the presence of iron powder at 20 C. yields a bromo-substituted trifiuoromethyl toluene XXII. Treatment of the latter with bromine in the presence of light and a peroxide catalyst yields the corresponding bromotrifiuoromethylbenzyl bromide XXIII.

C F 3 C F 3 Brz O Fe powder B r l MgB r CH3 CH XX XXI XXII B ml by Starting materials of formula II wherein R is phenyl, halo-substituted phenyl, alkyl-substituted phenyl, alkoxysubstituted phenyl or trifluoromethyl-substituted phenyl may be prepared by heating 3-(N-acetamido-N-nitroso) pyridine )OHV with benzene, halo-substituted benzene, alkyl-substiuted benzene, alkoXy-substituted benzene or trifluoromethyl-substituted benzene according to the procedure of Haworth et al., J. Chem. Soc., 1940, 372, and J. Chem. Soc., 1954, 4516. The product XXV is a 3-substituted pyridine wherein the N-acetamido-N-nitroso radical is replaced by a phenyl or substituted phenyl radical derived from the compound with which the 3-(N-acetamido- N-nitroso) pyridine is heated. The product of formula XXV is treated With sodamide according to the procedure of Chichibabin et al., J. Russ. Phys. Chem. Soc. 46, 1216 (1914), Chem. Zentr. H, 1064 (1915), to give the aminopyridines XXXII and XXXIII.

1 lon; I R e on xxrv R=halo alkyl,

alkoiry, or. NaNHg or hydrogen 0 NH? HQN O XXXIII XXXII Compounds of formula II wherein R is F, or wherein one R is F and the other R is alkoxy, may be prepared by treating 3-aminopyridine XXVI, or 3-alkoxy-5-aminopyridine, with amyl nitrite and fluoroboric acid according to the procedure of Roe eta1., JACS 69, 2443 (1947). The resulting 3-fiuoropyridine XXVII is then treated with sodamide according to the procedure of Chichibabin et al., J. Russ, Phys. Chem. Soc. 46, 1216 (1914), Chem. Zentr. II, 1064 (1915) to yield a mixture of 2-amino-3- fiuoropyridine and 2-amino-5-fluoropyridine which is separated by conventional procedures.

XXVI XXVII Z F Z =H, or alkoxy C Compounds of formula III wherein R is phenyl, halogen-substituted phenyl, alkyl-substituted phenyl, alkoxysubstituted phenyl, or trifiuorornethyl-substituted phenyl may be prepared by treating an amino-substituted 0-br0- mobenzoic acid XXVIII with acetic anhydride and then with nitrous acid. The resulting N-acetamido-N-nitroso-obromobenzoic acid XXIX is then treated with benzene or an R-substituted benzene wherein R is halogen, alkyl, alkoxy or trifluoromethyl according to the procedure of Haworth et al., supra. The aryl-substituted 0-bromobenzoic acid is then treated with LiAlI-L; or AlH according to known techniques to yield the corresponding aryl-substituted o bromobenzyl alcohol XXXI. The reaction sequence is as follows: H

Br 1) (CHaCO)2O Br 2) EN 2 I NH: N

fiCHa O XXVIII XXIX onion 0 OH Br" Br LiAlHi A1113 xxxr xxx The compounds of the present invention may be administered to mammalian species as central nervous system stimulants and as muscle relaxants. In the rat, responses to the stimulant activity of the compounds of the present invention include increased activity and body tremors. The muscle relaxant properties manifest themselves by responses that include decreased limb tone, decreased grip strength, and limb paralysis. In both the stimulant and muscle relaxant activities, the onset of activity is rapid, i.e., within about minutes; the activity persists for about 2 hours or longer. In the rat the dosage range varies from about 6.25 to about 50 mg./ kg. for both activities, while in humans the dosage range varies from about 40 to about 2000 mg. daily in about four divided doses for both activities.

In addition to serving as intermediates for the preparation of compounds of formula I, the pyridinium compounds of formula IV are themselves effective bactericides.

Microbial bioassays, as described in The Microbial World, by R. Y. Stanier, M. Doudoroif and E. A. Adelberg, Prentice-Hall, Inc., Englewood Cliffs, N.J., 3rd Ed., p. 858, are employed to determine the bactericidal properties of the pyridinium compounds IV of this invention. The bacteria employed include Staphylococcus aureus, 1, Streptococcus pyogenes, 2, Salmonella schottmuelleri, 3, Salmonella gallinarum, 4, Pseudomonas aeruginosa, 5, Proteus vulgaris, 6, Escherichia coli, 7, Pasturella multocida, 8, and Mycobacteriumtuberculosis, 9.

In the procedure, a sterile agar plate is seeded with the test organism, and then a number of glass cylindersare placed on its surface, forming a series of little cups. A known dilution of the compounds of this invention is added to each cup and the entire plate is then incubated until significant bacterial growth has occurred. The compounds of this invention diffuse out of the cup into the surrounding agar and produce a zone of inhibition. In this fashion it is possible to find the minimum inhibiting concentration (m.i.c.), of the compound that produces a recognizable zone of inhibition. The following summarizes the data.

M.i.c. of compound, micrograms, (mcg.)/m1.

Compound Compound Compound Compound oiE.l of x.1, otEx. of x Microorganism col. 3 col. 3 col. 3 col. 3

The compounds of the present invention in the described dosages may be administered orally; however, other routes such as intraperitoneally, subcutaneously, intramuscularly or intravenously may be employed.

The active compounds of the present invention are oral- 1y administered, for example,-with an inert diluent or with an assimilable edible carrier, or they may beenclosed in hard or soft gelatin capsules, or they may be compressed into tablets, orthey may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compounds of this invention may be incorporated with excipients and used in the form of tablets, troches, capsules, elixirs, suspensions, syrups, wafers, chewing gum, and the like. Such compositions and preparations should contain at least 0.1% of active compound. The percentage in the compositions and preparations may, of ocurse, be varied and may conveniently be between about 5% to about or more of the weight of the unit. The amount of active compound in such therapeutically useful compositions or preparations is such that a suitable dosage will be obtained. Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 10 and 200 milligrams of active compound.

The tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin may be added or a flavoring agent such as peppermint, oil of Wintergreen, or cherry flavoring. When the dosage unit form is a capsule, itmay contain in addition to materials of the above type a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit, for instance, tablets, pills or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compounds, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor. Of course, any material used in preparing any dosage unit form should be 'pharmaceutically pure and substantially non-toxic in the amounts employed.

The following examples illustrate the following invention without, however, limiting the same thereto. All temperatures are expressed in degrees Centigrade.

EXAMPLE 1 A. o-Bromobenzyl Bromide To 187.0 g. of o-bromobenzyl alcohol at room temperature, with stirring, is added dropwise, 271.0 g. of phosphorus tribromide. After the addition is complete, stirring is continued for three hours at room temperature. The mixture is then heated at -100" for three hours and poured into 6 kg. of crushed ice. The hydrolysis mixture is extracted with three 600 ml. portions of ether, the ether extracts are washed, dried, and concentrated to give 0- bromobenzyl bromide, b.p. about 132 (15 mm.).

B. o-Bromophenylacetonitrile To a suspension of 220.0 g. of sodium cyanide in 265 ml. of water and 380 ml. of absolute ethanol, is added, while stirring, a solution of 911.0 g. of o-bromobenzyl bromide in 911 ml. of ethanol. The reaction proceeds exothermally, but is eventually heated under reflux for about 0.5 hour, then cooled in an ice-bath, and filtered. The solid is washed with ether, the filtrate is concentrated, the residue is suspended in 300 ml. of water and extracted with three 500 ml. portions of ether. The ether extracts are washed, dried, and the solvent is removed. Theresidue is distilled to give 730 g. of the named product,,b.p. 141- 142 (12 mm.).

C. Ethyl-o-bromophenylacetate 9 while stirring, 740 ml. of concentrated sulphuric acid. The addition requires about two hours. The reaction mixture is heated under reflux for nine hours, poured into ice water, and extracted with 2.5 l. of ether. The ether extracts are washed, dried, and concentrated. The residue is distilled to give 780.0 g. of ethyl o-bromophenylacetate, b.p. 115 117 (4 mm), n 1.5434. i.

I, D. o-Bromophenethyl alcohol To a stirred suspension of 106.0 g. of lithium aluminum hydride in 3.7 1. of anhydrous ether, is added,,dropwise, a;

solution of 780.0 g. of ethyl o'bromophenylacetate in 3.1

l. of anhydrous ether. The reaction mixture is stirred'for about three hours and then heated under reflux for about five hours. The mixture iscooled, then threated dropwise with 800 nil. of water, and 1.511. of 10% aqueous hydrochloric acid. Theethefsolution.. is washed, dried, concentrated, and the residue is distilled to give 554.0 g. of 0- bromophenethyl alcohol, b.p. 130-'132 (8 mm.), a 1.5760.

. E. o-Bromophenethyl bromide f'F. 2-Amino-1-(o-bromophenethyl)pyridinium bromide To a solution of 212.0 of o-bromophenethyl bromide in 400ml. of dryxylene is added asolution of 120.0 g. of 2-aminopyridine in 400 ml. of dry xylene. The mix ture is heated under reflux for about three hours, cooled, and the xylene solution is decanted from the crystalline solid. The solid is triturated with 300 ml. of 2-propanol, filtered, and dried to give 138.0 g. of the product. The xylenesolution is again heated under reflux for 16 hours and by the same procedure, an additional 43.0 g. of product is recovered. The total of about 181.0 g. of product is "recrystallized from 2-propanol to give 170.0 g. of the title compound, m.p. about 195 -197.

gG. 11 l,12-Dihydropyrido[2,l-b] [1,3 lbenzodiazepine To a solution of 9.0 g. of 2-amino-1-(0-bromophenethyl)pyridinium bromide in 55 ml. of dimethylformamideis added 10.3" g. of micronized, anhydrous potassium carbonate and 0.5 g. of copperbronze. The mixture is heated at 100 for about three hours under nitrogen while stirring, and then is. filtered while hot. The filtrate is concentrated to dryness in vacuo to give about 8.6 g. of residue. This is extracted with two 125 ml. portions of boiling diisopropyl ether. The diisopropyl ether solution is treated with Darco, filtered, and concentrated to about 40 ml. to give on cooling, about 7.2. g. of 11,12- dihydropyrido[2,1-b] [l,3]benzodiazepine, m.p. about l22l24.

EXAMPLE 2 A. 2-Bromo-4methylthiobenzyl bromide 2-Bromo-4-methylthiobenzyl alcohol is prepared by the following sequence of reactions: 2-bromo-4-nitrobenzoic acid is reduced to 2Fbromo-4-aminobenzoic acid by means of iron and hydrochloric acid in aqueous ethanol. The 2-bromo-4aminobenzoic acid is diazotized with sodium nitrite in aqueous sulfuric. acid, and the diazonium compound treated with sodium methylmercaptide to give 2-bromo-4-methylthioben'zoic acid. The 2-bromo-4-methylthiobenzoic acid is converted to its methyl ester by heating under reflux with methanol-concentrated sulfuric acid, the methyl ester is isolated by ether extraction from the esterification mixture, recovered from the ether solution, distilled for purification, and reduced with lithium B. 3-(2-Bromo-4-methylthiophenyl)-1-propanol To a suspension of 25.0 g. of magnesium ribbon in a solution of 0.5 g. of iodine in 550 ml. of anhydrous ether is added 5 ml. of a solution of 296.0 g. of 4-methylthio-28-bromobenzyl bromide in 250 ml. of anhydrous ether. The reaction is initiated bygentle heating, and the remainder of the solution is then added dropwise so as to maintain a reflux. Subsequently, the mixture is heated and stirred under reflux for one hour, and then cooled to 10. A stream of nitrogen gas that has been cooled through a reservoir containing 48.0 g. of ethylene oxide is introduced into the reaction mixture. The addition of the ethylene oxide requires two hours. The mixture is subsequently stirred as it warms to room temperature, is stirred for four hours at room temperature, and then hydrolyzed by pouring on a mixture of 1 kg. of ice and 55.0 g. of ammonium chloride. Extraction with ether, followed by conventional workup of the ether solution, yields 210.0 g. of 3-(4-methylthio-2-bromophenyl)-1-propanol, b.p. about 125-127 (0.6 mm.).

C. 3-(2-Bromo-4-methylthiophenyl)propyl bromide To 49.0 g. of the product from (A), with stirring, is added, dropwise, 27.1 g. of phosphorus tribromide. The mixture is stirred subsequently for three hours at room temperature, then heated at -100" for three hours, and then poured into 1 kg. of crushed ice. Workup via ether extraction yields 52.7 g. of 3-(2-bromo-4-methylthiophenyl)propyl bromide, b.p. -102 (0.8 mm.).

D. 2-Arnino-1-[3-'(Z-bromo-4-methylthiophenyl) propyl] -pyridinium bromide To a solution of 154.0 g. of 3-(2-bromo-4-methylthiophenyl)propyl bromide in 400 ml. of dry xylene, is added a solution of 70.0 g. of 2-aminopyridine in 300 ml. of dry xylene and the mixture is heated under reflux for about eighteen hours. The cool xylene solution is decanted from the crystalline solid, the solid is triturated with 200 ml. of 2-propanol and filtered to give 117.0 g. of crude product. Recrystallization of the latter from 2-propanol gives about 98.0 g. of 2-amino-1-[3-'(2-bromo- 4-methylthiophenyl)propyl] -pyridinium bromide.

E. 12, 13-Dihydro-3-methylthio-1 lg-pyrido- [2,1-b] [1,3 -benzodiazocine To a solution of 8.1 g. of 2-amino-1-[3-( 2-bromo-4- methylthiophenyl)propyl1pyridinium bromide in 50 ml. of dirnethylformamide is added 10.3 g. of micronized, anhydrous potassium carbonate and 0.5 g. of copper bronze. The mixture is heated at 100 for about three hours under nitrogen while stirring, and then it is filtered hot. The filtrate is concentrated to dryness in vacuo to give about 9.0 g. of residue. This is extracted with two ml. portions of boiling di-isopropyl ether. The solution is treated with Darco, filtered, and concentrated to about 35 ml.. This on cooling givesabout 4.3 g. of 12,13- dihydro 3 methylth'io 11g pyrido[2,1-b] [1,3]benzodiazocine. I

' EXAMPLES 3-17 Following the procedure of example 1 (A) but substituting an equivalent amount of the'substituted o bromobenzyl alcohol in column 1 for o-bromobenzyl alcohol, there isobtained respectively, the corresponding o -bromophenethyl bromide indicated in column 2. Reaction of the latter with Z-aminopylridine following the procedure of example 1 (F) yields, respectively, the pyridinium compound indicated in column 3. Treating the latter with K CO and copper bronze following the procedure ;of example 1 (G) yields, respectively,'the final product'of column4.

stituted Z-aminopyridine in column 1, there is obtained, respectively, the quaternary derivative shown in column 2. Treatment of the latter as described in example 1 yields, respectively,'the final compound indicated in column 3.

EXAMPLES 18-37 Following the procedure of example 1, but substituting for Z-aminopyridine an equivalent amount of the sub- CHii-CH:

Hr-CH:

o c c H H m m m m C N N m AQV 0 m m w m m m o N w m m o AQ Aov a k 1 m o m w m W M m n W M M m m u n n u m N mm L L m m m M M M 19 TABLE-Continued Example number 1 2 3 34.

o o NH: NH: m N

Br I Q Q CH2CHI e N NH: 631? NHz B1 S N 2)2-- 0 CHgCHz V t 9 CHg(CHz) NH: CH (CH2)0 NH2 '31 N 37.- ((|JH2)5CH: ((THzhCHs (CHzhCH:

on,-or3 G N N NH: NHz -Br G9 H2)z EXAMPLE 38 tion is washed, dried, and concentrated in vacuo to give l1,12-Dihydropyrido[2,l-b] [1,3 J-benzodiazepine EXAMPLE 39 A. 1,2-Dihydro-2-imino-l-(o-bromophenethyl) pyridine To a solution of 3.3 g. of sodium methoxide in 120 ml. of anhydrous methanol is added 10.8 'g. of 2-amino-1-(obromophenethyl)pyridiniurn bromide, prepared as de-.. scribed in example 1 (G). The solution is stirred under nitrogen for 2 hours and then heated under reflux for 5 hours. The solvent is removed in vacuo and the residue is treated with 200 ml. of anhydrous ether. The ether soluabout 6.8 g. of yellow solid. This is recrystallized from hexane to give the name product, mp. 68-70.

B 11,12-Dihydropyrido[2,l-b] [1,3 benzodiazcpine To a solution of 5.6 g. of 1,2-dihydro-2-imino-l-'(obromophenethyl)pyridine in ml. of xylene is added 2.8 g. of potassium carbonate and 0.5 g. of copper bronze and the mixture is heated under reflux for 3 hours, and filtered. The filtrate is concentrated .inyacuo and the residue recrystallized from diisopropyl ether to give about 2.3 g. of the title product, m.p. about 122-124".

EXAMPLES 40-42 Following the procedure of example 1 (B) through 1 (G) butv substituting the o-bromophe nethylbromidein column I below for the o-brornobenzyle bromide in part B, and substituting for 2-aminopyridine in part F, the compound listed in column II, there is obtained (from part F) the pyridinium compound listed in column III and (from part G) the benzodiazocine compound listed in column IV.

Ex: 7 v M No. I 11 III [I 40. 01 or on on 01 on on HaC- omornnr e a 2 lQ O N Br I 0 NE; NH, Br .Br \N OCH; N 0cm OIN(CH3CH3)3 indicated III v CHaCHzO a Q r NH2 Br (0115 G3/ N NH B NH, soimcmcnm respectively, the quaternary derivative shown in column 2. Treatment of the latter as described in example 1 yields, respectively, the final compound CH2) a TABLE-Co-ntinued the subthere is obtained, 30 in column 3.

CH; omomm 1 F Br 0 z\ CHaCHzBl' (9H3 CH1 *EXAMPLES 43-50 Following the procedure of example 1 but substituting :;-'-::::-'.J:-'::IIII-:;::::

42"--. (CHICHDZNSQ stituted 2-amin0pyridine in column 1,

Example number for Z-aminopyridine an equivalent amount of Example number (CH2): H30 33/ lBr H2 Bt CH2): H50 69) NH: Br

m m N- N Qvu Q o m m H mm .m T L 2 m m J.. I 5 mm in f 7, 2 L I x u a C CH:O N

3): F N/ tut TABLECntinued III Example number BrfN-(Cl-h) I I E. n: T2 ez' EXAMPLE 63 Preparation of capsule formulation Ingredient: Milligrams per Capsule 11,12 Dihydropyrid0[2,1-b] [1,3]benzodiazepine 400 Starch Magnesium stearate S The active ingredienL fstarcli and magnesium stea'ra'te are blended together. The mixture is used to fill hard-shell capsules of a suitable size at a fill weight of 485 milligrams per capsule.

EXAMPLE 64 W The active ingredien tQIactOseand corn starch (for mix) are blended together. The'corn starch (for paste) is suspended in water at a ratio of 10 grams of corn starch per 80 milliliters of waterland heated with StlI'I'iIlgvtO form a paste. This paste is thenfused to granulate the mixed powders. The wet granules are passed through a No. 8 screen and dried at 120 F. The dry granules are passed through a No. 16 screen. The mixture is lubricatedwith magnesium stearate and compressed into tablets. in aEsuitable tableting machine. Each tabletcontains 300 milligrams of active ingredient. s ,Y

EXAMPLE 65 Preparation of oral syrup formulation Ingredient: Amount (mg) 1l,l2-Dihydropyrido[2,1-b][l,3]benzodiazepine 500 Cherry flavor Distilled water q.s. to mL t The sorbitol solution is added to 40 milliliters of distilled water and the active ingredient is suspended therein. The sucaryl, saccharin, sodium benzoate, flavor and dye are added and dissolved in the above solution. The volume is adjusted to 100 milliliters with distilled water.

Other ingredients may replace those listed in the above formulation. For example, a suspending agent such as bentonite magma, tragacanth, carboxymethylcellulose, or methylcellulose may be used. Phosphates, citrates or tartrates may be added as buffers. Preservatives may include the parabens, sorbic acid and the like and other flavors and dyes maybe used.in place of those listed above.

What is claimed is: a 1. A compound of the formula:

wherein m is 1 or 2; R is the same or different and 'may be hydrogen, F,"Cl, or Br, alkyl of from 1 to 4 carbon atoms, al koxy of 29 30 from 1 to 4 carbon atoms, alkylthio of from 1 to 4 carbon atoms, alkoxy of from 1 to 4 carbon atoms carbon atoms, benzyl, phenethyl, phenyl, phenylthio, or trilluoromethyl, and or mono-substituted phenyl wherein the substituent n is 2or 3. may be F, Cl, Br, I, alkyl of from 1 to 4 carbon 2. A compound of claim 1 having the name 11,12- atoms, alkoxy of from 1 to 4 carbon atoms, or tri- 5 dihydropyrido[2,1-b][1,3]benzodiazepine. fiuoromethyl; provided that when R is halogen, R 3. A compound of claim 1 having the name 12,13- occupies only the 3- or 5-positions with respect to the dihydro 3 methylthio 1111 pyrido[2,1-b] [1,3]- pyridyl nitrogen as the 1-position, benzodiazocinc. R is hydrogen, F, Cl, Br, 1, alkyl of from 1 to 9 carbon References Cited atoms, alkox-y of from 1 to 4 carbon atoms, alkyl- 10 UNITED STATES PATENTS thio of from 1 to 4 carbon atoms, alkylsulfonyl wherein the alkyl radical has from 1 to 4 carbon 3,565,914 2/1971 Yale et a1 260-4943 B atoms, phenyl, phenyloxy, sulfamoyl, dialkylamidosulfonyl wherein each alkyl radical has from 1 to 4 carbon atoms, trifluoromethyl, mono-substituted 15 US Cl XR phenyl or mono-substituted phenyloxy wherein the substituent is F, Cl, Br or I, alkyl of from 1 to 4 260294.8 F, 294.8 G, 296 R, 296 H ALAN L. ROTMAN, Primary Examiner Column 11, example 6, golumn 3, .B

"Zg; gf ,'L' -is- Um-TE'D STATES PATENT OFFICE v v CERTIFICATE OF CORRECTION 3,825,549 July 23., 1974 Patent No. Dated Inventofls) Harry LOUIS Yale et al.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 2, line 13 "phenloxy should read phenyloxy.

Column 2, line 35, "or" should read of--. Column 4, formula XI, "Rr" should read -Br-.

Column 9, line 15, "threated" should read -treated--.

Column 10, line l0, "28" should reag -2-. e

" should read .Br

Example 7, delete ".Br from column 4 and insert in column 3 Example 8, delete ".Br from column 4, and insert in column 3.

'-- a p 1 Column "12L should read j-GF Example 15, column 4, "CH CH should read CH -CH Example 16, delete .Br from column 4 and insert in column 3. Column 20, line 60, "9-bromobenzyle" should read bromobenzyl--. Example 41, column II, "CH should read C'3H Q I 9 Example 42, column I,"(CH CH NSO should read --(CH CH NSO 2 Example 48, column 3, (CH should read ---(CI-I Column 28, example 65, line 42, "40" should read 40 ml..

Signed and sealed this 15th day of October 1974.

(SEAL) Attest:

McCOY M. GIBSON JR. C. MARSHALL DANN Attesting Officer Commissioner of Patents 

